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Biomedical subjects

P Frost

Publications and source records attributed to P Frost.

At least 109 records · Page 6Linked to original sources
PubMed1988

Induction in a murine tumor of immunogenic tumor variants by transfection with a foreign gene.

Transfection of the undifferentiated murine colon carcinoma line CT-26 with the gene coding for the hemagglutination antigen (HA) of influenza virus resulted in the generation of highly immunogenic tumor cells. CT-26 cells transfected with HA not only failed to grow in syngeneic mice but also protected normal animals against a challenge with otherwise lethal doses of parental nontransfected cells. The immunogenicity of HA-transfected cells appeared to correlate with surface HA expression in that tumorigenic clones of HA-transfected CT-26 cells expressed little HA, while immunogenic clones were high expressers of HA. Irradiation of immunogenic HA clones did not abrogate their immunogenicity. These observations demonstrate that immune recognition of a poorly immunogenic tumor can be produced by immunization with tumor cells expressing a defined, foreign cell surface antigen.

Animals↗
PubMed1988

Pitfalls and practice of Luria-Delbrück fluctuation analysis: a review.

Luria-Delbrück fluctuation analysis provides a method to estimate mutation rates in cell populations. Originally designed for bacterial populations, the method now is widely applied in somatic cell genetics and in cancer biology. However, there are fundamental genetic differences between bacteria and somatic cells, and this together with the inherent mathematical complexity of fluctuation analysis can lead to many pitfalls in its application. In addition there is considerable statistical error associated with the method. The use, misuse, and limitations of fluctuation analysis are reviewed here with the hope that such problems may be avoided.

Cells, Cultured↗
PubMed1988

The prevalence of ouabain-resistant variants after mutagen treatment. Lack of correlation between the frequency of variant expression and the metastatic phenotype.

In order to test the hypothesis that tumor cells with greater malignant potential should have an increased sensitivity to mutagens, four individual murine cell lines, each paired for their metastatic and nonmetastatic potentials, were compared with respect to the prevalence at which ouabain-resistant mutants could be obtained after treatment of the cells with the mutagen MNNG. No increase in the prevalence of induced mutation in metastatic cells was observed; and, in fact, in two cases (h-ras-transfected 3T3 and SP1 cells), nonmetastatic cells had a higher prevalence of mutations after MNNG treatment than did their metastatic counterparts. We suggest that the absolute level of genomic instability, measured by this means, is not critical to malignant potential and tumor progression.

Animals↗
PubMed1987

Spontaneous mutation rates in cloned murine tumors do not correlate with metastatic potential, whereas the prevalence of karyotypic abnormalities in the parental tumors does.

We tested the hypothesis that highly malignant cell lines are genomically more unstable than their less malignant counterparts, and that this instability is more pronounced in clones than in cell lines. We compared MDAY-D2 to its non-metastatic variant, D36W25, with regard to (1) the rate of development of ouabain resistance within parallel clones and (2) the prevalence of G-banded karyotypic abnormalities. We detected no significant difference between the spontaneous mutation rates for ouabain resistance. However, the MDAY-D2 cell line possessed both a higher prevalence and greater diversity of chromosomal abnormalities. One possible explanation for these seemingly inconsistent results is that genomic instability may remain essentially constant throughout tumor progression, whereas an accumulation of genetic changes may be responsible for the observed increased prevalence of abnormalities and the development of selective survival advantages during progression.

Animals↗
PubMed1987

Immunogenic variants of a murine fibrosarcoma induced by mutagenesis: requirement of viable cells for antigen-specific cross-protection.

The purpose of the study was to investigate the immunological and biological consequences of neoantigen expression by immunogenic tumor variants (Imm+) following in vitro treatment with the mutagen 1-methyl-3-nitro-1-nitrosoguanidine. The weakly immunogenic murine fibrosarcoma MCA-F was used because we have previously characterized the tumor-specific transplantation antigen expressed by this tumor. Immunogenic variant clones were obtained at high frequency following four treatments with 1-methyl-3-nitro-1-nitrosoguanidine. The immunogenicity of the Imm+ clones was confirmed by their progressive growth in immunosuppressed C3H/HeN mice and their lack of growth in normal syngeneic (C3H/HeN mice. The immune response engendered in immunocompetent mice after a single immunization with viable Imm+ cells was tumor specific, completely protecting hosts against challenge with 10,000-fold the minimum tumorigenic dose of parental MCA-F cells, but not against 10 minimum tumorigenic doses of the non-cross-reactive tumor MCA-D. The strong cross-protection elicited by Imm+ neoantigens against the parental tumor-specific transplantation antigen was not observed when soluble extracts or isolated plasma membranes of Imm+ cells were used for immunization. Immunogenic variant cells inactivated using either mitomycin C or gamma-irradiation also demonstrated a significantly diminished immunoprotective activity against challenge with the parent tumor. However, inactivated Imm+ cells and their isolated plasma membranes still expressed sufficient neoantigen to completely protect mice against homotypic Imm+, but not parental challenge. These results suggest that (a) the MCA-F Imm+ variants express neoantigens capable of engendering a strong specific as well as cross-protective immunity against challenge with either the parent or the variant and (b) the associative recognition of neoantigen and TSTA that results in strong cross-protection against challenge with the parent tumor requires immunization with viable Imm+ cells for full expression of the immunogenic phenotype.

Animals↗
PubMed1987

Rate of generation of major karyotypic abnormalities in relationship to the metastatic potential of B16 murine melanoma.

To test the hypothesis that genetic instability correlates with malignant potential, we compared the rate of generation of marker chromosomal abnormalities in clones of B16 F1 and B16 F10 murine melanoma. These rates were estimated through an adaptation of fluctuation analysis of Luria and Delbruck (S. E. Luria and M. Delbruck, Genetics, 28: 491-511, 1943). The highly metastatic F10 line showed the same degree of marker chromosomal instability as the poorly metastatic F1 line (0.01 variants/cell/generation). When subclones of a karyotypically unstable F10 clone were compared with those of a more stable F10 clone, both groups caused the same number of pulmonary metastases, thus demonstrating a further lack of correlation of malignant potential with the level of genomic instability. Since measurements based on marker chromosomes may not truly reflect all of the changes detectable by G-banding, we also analyzed the G-banded karyotypes of the cell lines and their clones (chromatid or chromosomal breaks were not considered in this study). The F10 clones possessed an additional copy of chromosome 1 and also a significantly higher prevalence of the translocation t(9,12) when compared with the F1 clones. Rather than general rates of major karyotypic change determining tumor progression, we suggest the importance of other genetic or epigenetic mechanisms, particularly subtle nonrandom genetic or molecular changes, as the determining factors for malignant potential.

Animals↗
PubMed1987

Selection of metastatic variants with identifiable karyotypic changes from a nonmetastatic murine tumor after treatment with 2'-deoxy-5-azacytidine or hydroxyurea: implications for the mechanisms of tumor progression.

Experiments were undertaken to explore whether in vitro exposure of a nonmetastatic murine tumor to chemotherapeutic drugs would affect the ability of this tumor to metastasize spontaneously. The tumor chosen was an aneuploid (near-tetraploid) spontaneously arising intraductal mammary adenocarcinoma (CBA-SP1), which normally fails to give rise to microscopic or macroscopic metastases after s.c. inoculation of cells. The drugs tested were 5-aza-2'-deoxycytidine (5-aza-dCyd) and hydroxyurea. We found that the injection of 1 X 10(5) uncloned drug-treated cells s.c. resulted in the emergence of gross and/or microscopically detectable metastases in the lungs of CBA mice. Individual clones derived from hydroxyurea-treated cells all produced metastases in a manner similar to the bulk culture injections. Clones of 5-aza-dCyd-treated cells also produced metastases, but fewer of these produced macroscopic metastases. In addition, only 9 of 15 5-aza-dCyd-treated clones produced tumor takes because of the ability of 5-Aza-dCyd to engender Imm+ variants in CBA-SP1 cells. Lung metastases obtained after the injection of uncloned cells retained their metastatic phenotype for three generations, indicating that the phenotypic change was a heritable characteristic. Although the genetic or epigenetic mechanism for this change is unknown, we observed karyotypic changes of a similar nature in the drug-treated cell lines established from micrometastases. These involved the detection of extra copies of chromosome 8. It is possible that exposure of tumors to therapeutic agents may in some cases increase their aggressiveness through genetic or epigenetic mechanisms that lead to high frequency heritable phenotypic alterations associated with distinguishable chromosomal changes.

Animals↗
PubMed1987

Natural killer cell activity of prostatic cancer patients.

Natural killer (NK) cell activity of prostatic cancer patients was compared with that of control groups by the radioactive indium (111In) release assay using the K562 and H494 cells as targets. Patients suffering from advanced prostatic cancer (clinical stages C and D) exhibited significantly lower NK activity against K562 cells (28 +/- 18%) than did the normal group (41 +/- 19%). The lower NK activity of these patients is not related to their age, since patients in the same age range with localized cancer (stage B) or benign prostatic hyperplasia did not show low NK activity (37% +/- 19%). This lower NK activity is not due to a depletion of the NK cell precursor population, since the NK activity of advanced cancer patients improves significantly after in vitro incubation with interferon. The NK activity of normal subjects or patient groups showed wide fluctuations during the 18-month observation period. Because of these interassay variations, it is necessary to use standard control subjects during long-term monitoring of the NK activity of the patients.

Age Factors↗
PubMed1987

Experimental metastasis: a novel application of the variance-to-mean power function.

An empiric power function relationship between a population's mean density (m) and its corresponding variance (v), written v = a.mb (a, b, constants), may be applied to the analysis of experimentally induced pulmonary metastases within syngeneic (C57BL/6 X C3H)F1 mice. The mean and variance of the numbers of resultant B16 F1 and B16 F10 melanoma metastases strongly correlated with the power function (r2 greater than 0.8). The exponent b was 1.4 +/- 0.1 and 1.6 +/- 0.2 for the F1 and F10 melanomas, respectively, indicating a clustering of metastases within certain mice. This clustering of metastases within more highly affected animals may reflect a diffusion-limited aggregation of tumor cells within the circulation and the resultant greater ability of these aggregates to form metastases.

Animals↗
PubMed1986

Biology of metastasis.

The acquisition by tumor cells of the ability to metastasize is the critical event in the clinical course of most human neoplastic disease. While metastasis plays a pivotal role in the ultimate success of failure of therapy, it is in fact a result of a more insidious malignant process termed tumor progression. It is the progression of tumors from a less to a more malignant phenotype that results in tumor heterogeneity and the selection of cells with a more malignant (metastatic) phenotype. The development of metastases is thus integrally related to the mechanisms of tumor progression, which in turn is likely due to the instability of the tumor cell genome. The authors' thesis is that metastatic tumor cells are a selected population derived from a heterogeneous parent tumor which contains many clones with different phenotypes. This discussion will, therefore, address the role of tumor genomic instability as a basis for the selection of metastatic cells.

Animals↗
PubMed1986

Periodontal disease. Etiology and pathogenesis.

Periodontal disease is the number-one cause of the early loss of teeth in dogs and cats. Some of the factors in the adult animal that play a major role in the development of periodontal diseases are discussed in this article, including overcrowding, malocclusions, diet, developmental defects, and metabolic and systemic disease.

Animals↗
PubMed1986

Feline dental disease.

Periodontal disease and chronic gingivitis/stomatitis are the most common feline dental diseases. With routine dental care and increased emphasis on home oral hygiene, these diseases can be controlled. Cats can be seen with a number of other dental disorders, and improved treatment methods such as restorations of early subgingival resorptive lesions, endodontic therapy, and orthodontic therapy can be performed successfully. More study and research are necessary about the gingivitis/stomatitis syndrome and subgingival resorptive lesions so that improved prevention and treatment recommendations can be made.

Animals↗
PubMed1986

On the possible contribution of DNA hypomethylation to the induction of high frequency and heritable drug-induced alterations in the malignant phenotype.

A hypothesis is presented that anti-neoplastic agents can alter gene expression at very high frequencies, even in vivo, by altering DNA methylcytosine levels and/or patterns. Such changes can be inherited, either in a stable or unstable manner, and can lead to the generation of more, or less, malignant variants, depending upon the gene(s)-that is (are) affected. An experimental model is reviewed to support this hypothesis in which it is shown that thymidine kinase activity in (TK-) deficient tumor cell mutants can be switched on when exposed to the anti-neoplastic drug and potent demethylating agent, 5-azacytidine in vivo. The implications of these results are discussed in relation to the possible promoting effects of anti-cancer therapies on the development of tumor cell heterogeneity, tumor progression and tumor cell dissemination.

Alkylating Agents↗